The commonly used method of oral contraception in human females consists of a combination of estrogen and progestin (progestational agent) administered daily for 21 days. Menstruation occurs about 3 to 5 days after withdrawal and administration is reinitiated after 8 days, thereby beginning a new cycle. Inhibition of ovulation by the progestin is believed to be the primary effect of this contraceptive method. Rudel, et al., Fertility and Sterility, 16, 158-169, (1965) pointed out, however, that progestins, in addition to their antiovulatory action, have other antifertility effects including the production of a state of maturation of the endometrium which is out of phase with ovulation, accompanied by changes in the cervical mucus, these changes being incompatible with vital and motile spermatozoa. The authors suggested that, in an oral contraceptive agent comprising a combination of progestin and estrogen, these other effects (in addition to inhibiting ovulation) of progestins may be lost in the presence of added estrogen. Martinez-manaoutou, et al., ibid, 17, 49-57 (1966) has also suggested that a low dose of a progestin, specifically chlormadinone acetate--a progestin without estrogenic activity--prevented conception when administered continuously at the rate of 0.5 mg. per day to human females during an entire ovulatory cycle. It was determined that ovulation probably occurred in 60 percent of the patients. Only one pregnancy occurred in 416 patients and 1600 menstrual cycles. From these observations, the authors advocated the continuous administration of minimal doses of a progestin as a contraceptive method in human females. The same laboratory reported, ibid, 17, 57-62 (1967) that chlormadinone acetate when administered to human females at a dosage of less than 500 mcg. daily demonstrated anti-estrogenic influence on the cervical mucus without suppression of endometrial development. The contraceptive effectiveness of the administered progestational agent appeared to parallel closely the changes in the cervical mucus. The same research group repeated in ibid, 18, 219-221 (1967) their previous findings that a progestin given at dose levels which do not inhibit ovulation is able to create a state of hormonal imbalance as evidenced by a suppressed endometrium and/or a thickened, scanty cervical mucus. The daily low level administration of a progestin throughout the menstrual cycle was the contraceptive method advocated by the authors for human population control on a large scale, and they specifically advocated the employment of an implanted pellet which would meter out the progestin for a month or six weeks. The authors also advocated the administration of estrogens after ovulation has occurred in the hope that such administration would create another hormonal imbalance hostile to conception and thus promote contraception. In summary, this research group has found that the low daily dosage of chlormadinone acetate (0.5 mg. daily), a progestin without estrogenic activity, throughout the menstrual cycle afforded a contraceptive method with an efficacy comparable to the well-known marketed estrogen-progestin combinations.
Ufer, et al., U.S. Pat. No. 3,758,687 issued Sept. 11, 1973 covers the administration to a female human at some point during the interval from the 5th to the 8th day of the menstrual cycle of a depot formulation of a progestin so as to prevent conception during the remainder of the cycle and possibly for 2-3 cycles. The depot formulation pays out the progestin continuously so that there is a measureable amount present for at least one cycle and perhaps longer. Kincl, U.S. Pat. No. 3,822,355 discloses the administration of a progestational agent only during the luteal phase of the menstrual cycle. Schmitt, et al. Chemical Abstracts, 77, 10849 (1972) disclose the continuous administration of a gestagen, specifically chlormadinone, at low levels (minipills). The regimen employed was a failure since half of the thirty-five women in the test group showed bleeding disturbances. Rudel, U.S. Pat. No. 3,828,106, discloses an oral pharmaceutical form for administering steroid hormones.
A relationship between the progestational state of the uterus and implantation was reported originally by Corner and Allen, Am. J. Physiol., 86, 74 (1928), 88, 340 (1929). The necessity of pretreatment with the follicular hormone (estrogen) for optimal response to the luteal hormone (progesterone) was later observed by many others including Allen, Am. J. Physiol., 92, 612 (1930) and Hisaw and Leonard, Am. J. Physiol., 92, 574 (1930). The phenomenon of sequential influence of ovarian steroids is now widely accepted by research workers studying mammalian reproductive cycles.
Estrogen priming is apparently not indispensable for a response to a progestin, but the priming lowers the threshold for progestational responses including progestational proliferation, increased carbonic anhydrase, Pincus et al. Endocr., 61, 528 (1957), and synthesis of DNA and mitosis, Lee and Dukelow, J. Reprod. Fert., 31 473 (1972). Rudel, et al., J. Reprod. Fert., 8, 305 (1964), observed that the progestational response to chlormadinone acetate, a typical progestin, in humans is directly related to the degree of estrogen stimulation of the endometrium at the time treatment is started.